Nitric oxide (nitrogen monoxide, NO) is subject to oxidation in vivo, which results in the production of reactive species that either form nitrogen oxide-containing adducts, oxidized cellular components, or relatively unreactive oxyanions. Among the biological actions of NO, nitrosation (the chemistry of the one-electron oxidized species nitrosonium (NO+)) has historically (and undoubtedly) received the most attention in terms of chemical pathology. Nitrosation of nucleophilic cellular targets results in both damaging (e.g., nitrosamine formation and DNA base deamination) and also possible regulatory effects (formation of nitrosothiols). However, the mechanism(s) whereby nitrosation takes place in cells is unknown. Our overall objective is to define the biochemical mechanism(s) of nitrosation from NO. To accomplish this objective, we will proceed along two lines (encompassing our four Specific Aims), based on our previous work in these two areas.
In Aims I -II, we will delineate the kinetic and mechanistic characteristics of the reaction of NO with O2 within hydrophobic environments such as membranes. We have previously proposed that this is the major site biologically for this reaction that produces potent nitrosating species. We will determine the kinetic characteristics of this effect, which we have estimated accelerates the NO/O2 reaction by a factor of approximately 300-fold under biological conditions. In addition, we will examine the mechanistic effects of this partitioning, specifically, the solvation and collisional effects which the hydrophobic interior of membrane bilayers may have in influencing these reactions between small uncharged radical species (as opposed to reactions in aqueous solution).
In Aims I ll-IV, we will delineate the characteristics of non-erythroid cellular O2-dependent consumption of NO, which is quantitatively the major transformation of NO that occurs outside the vascular lumen, and which we have shown results in the production of nitrite (a marker for nitrosative chemistry). This phenomenon is distinct from the membrane effect in Aims I-II, and we will identify the biochemical mechanism(s) of this reaction, including the cellular species involved and nature of the oxygen species responsible for NO oxidation (dioxygen or superoxide) as well as the involvement of transition metal ions. We will also delineate the nitrosative cellular chemistry from both exogenous and endogenous NO. These studies will provide both new insight into the basic biochemistry of NO and its derivatives, and also potentially provide new possible avenues for therapeutic development in a variety of pathological conditions, including carcinogenesis, inflammatory stimulation, and oxidative stress.
| Möller, Matías N; Li, Qian; Chinnaraj, Mathivanan et al. (2016) Solubility and diffusion of oxygen in phospholipid membranes. Biochim Biophys Acta 1858:2923-2930 |
| Kushwaha, Meenakshi; Anderson, Joel M; Bosworth, Charles A et al. (2010) A nitric oxide releasing, self assembled peptide amphiphile matrix that mimics native endothelium for coating implantable cardiovascular devices. Biomaterials 31:1502-8 |
| Vitturi, Dario A; Teng, Xinjun; Toledo, José C et al. (2009) Regulation of nitrite transport in red blood cells by hemoglobin oxygen fractional saturation. Am J Physiol Heart Circ Physiol 296:H1398-407 |
| Bosworth, Charles A; Toledo Jr, Jose C; Zmijewski, Jaroslaw W et al. (2009) Dinitrosyliron complexes and the mechanism(s) of cellular protein nitrosothiol formation from nitric oxide. Proc Natl Acad Sci U S A 106:4671-6 |
| Li, Qian; Lancaster Jr, Jack R (2009) Calibration of nitric oxide flux generation from diazeniumdiolate *NO donors. Nitric Oxide 21:69-75 |
| Toledo Jr, Jose C; Bosworth, Charles A; Hennon, Seth W et al. (2008) Nitric oxide-induced conversion of cellular chelatable iron into macromolecule-bound paramagnetic dinitrosyliron complexes. J Biol Chem 283:28926-33 |
| Chen, Lan; Bosworth, Charles A; Pico, Tristant et al. (2008) DETANO and nitrated lipids increase chloride secretion across lung airway cells. Am J Respir Cell Mol Biol 39:150-62 |
| Griguer, Corinne E; Oliva, Claudia R; Gobin, Eric et al. (2008) CD133 is a marker of bioenergetic stress in human glioma. PLoS One 3:e3655 |
| Kelley, Eric E; Batthyany, Carlos I; Hundley, Nicholas J et al. (2008) Nitro-oleic acid, a novel and irreversible inhibitor of xanthine oxidoreductase. J Biol Chem 283:36176-84 |
| Teng, Xinjun; Scott Isbell, T; Crawford, Jack H et al. (2008) Novel method for measuring S-nitrosothiols using hydrogen sulfide. Methods Enzymol 441:161-72 |
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